ArticleNature chemical biology2023
Base editor scanning charts the DNMT3A activity landscape.
Article in Nature chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 45 citations in OpenAlex.
- Systematic Targeting of Protein Complexes with Molecular COUPLrs.Cancer discovery · 2026Article
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- Inducible, split base editors for in vivo cancer functional genomics.Nature biotechnology · 2026Article
- Determinants of metal import and specificity in a bacterial transporter.bioRxiv : the preprint server for biology · 2026Article
- DNMT3A R882H Is Not Required for Disease Maintenance in Primary Human AML but Is Associated with Increased Leukemia Stem Cell Frequency.Cancer discovery · 2026Article
- A functional map of CDK-drug interactions at single amino acid resolution.bioRxiv : the preprint server for biology · 2025Article
- Activity-based selection for enhanced base editor mutational scanning.Nature genetics · 2025Article
- Article
- Fueling chromosomal gene diversification and artificial evolution with CRISPR.Genome biology · 2025Review
- Multimodal scanning of genetic variants with base and prime editing.Nature biotechnology · 2025Article
- Orthogonal resistance mechanisms of classical- and induced-proximity inhibitors.bioRxiv : the preprint server for biology · 2025Article
- Article
- Histone modification-driven structural remodeling unleashes DNMT3B in DNA methylation.Science advances · 2025Article
- MultiplexedbioRxiv : the preprint server for biology · 2025Article
- Characterization of Rationally Designed CRISPR/Cas9-Based DNA Methyltransferases with Distinct Methyltransferase and Gene Silencing Activities in Human Cell Lines and Primary Human T Cells.ACS synthetic biology · 2025Article
- Base editing screens define the genetic landscape of cancer drug resistance mechanisms.Nature genetics · 2024Article
- Using human disease mutations to understand de novo DNA methyltransferase function.Biochemical Society transactions · 2024Review
- Genomics 2 Proteins portal: a resource and discovery tool for linking genetic screening outputs to protein sequences and structures.Nature methods · 2024Article
- Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.Cancer discovery · 2024Article
- Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor.Science (New York, N.Y.) · 2024Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
DNA methylation is critical for regulating gene expression, necessitating its accurate placement by enzymes such as the DNA methyltransferase DNMT3A. Dysregulation of this process is known to cause aberrant development and oncogenesis, yet how DNMT3A is regulated holistically by its three domains remains challenging to study. Here, we integrate base editing with a DNA methylation reporter to perform in situ mutational scanning of DNMT3A in cells. We identify mutations throughout the protein that perturb function, including ones at an interdomain interface that block allosteric activation. Unexpectedly, we also find mutations in the PWWP domain, a histone reader, that modulate enzyme activity despite preserving histone recognition and protein stability. These effects arise from altered PWWP domain DNA affinity, which we show is a noncanonical function required for full activity in cells. Our findings highlight mechanisms of interdomain crosstalk and demonstrate a generalizable strategy to probe sequence-activity relationships of nonessential chromatin regulators.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.